Molecular Medicine

, Volume 20, Issue 1, pp 72–79 | Cite as

Recent Developments in the Role of High-Mobility Group Box 1 in Systemic Lupus Erythematosus

  • Fleur Schaper
  • Johanna Westra
  • Marc Bijl
Review Article


High-mobility group box 1 (HMGB1) is an important molecule for several nuclear processes. Recently, HMGB1 has gained much attention as a damage-associated molecular pattern (DAMP) and has been implicated in the pathogenesis of several (auto)-immune diseases, in particular, systemic lupus erythematosus (SLE). A main pathogenic feature in SLE is the accumulation of apoptotic cells. Since HMGB1 is released from apoptotic cells it has been hypothesized that HMGB1 might fuel the inflammatory processes, as seen in this disease, and play a fundamental role in the pathogenesis. In this review, we discuss evidence in support of the theory that HMGB1 is an important mediator in SLE and may be considered a new autoantigen.


  1. 1.
    Bickerstaff MC, et al. (1999) Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nat. Med. 5:694–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Botto M, et al. (1998) Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat. Genet. 19:56–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Sanford AN, Dietzmann K, Sullivan KE. (2005) Apoptotic cells, autoantibodies, and the role of HMGB1 in the subcellular localization of an autoantigen. J. Autoimmun. 25:264–71.CrossRefPubMedGoogle Scholar
  4. 4.
    Perniok A, Wedekind F, Herrmann M, Specker C, Schneider M. (1998) High levels of circulating early apoptic peripheral blood mononuclear cells in systemic lupus erythematosus. Lupus. 7:113–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Courtney PA, et al. (1999) Increased apoptotic peripheral blood neutrophils in systemic lupus erythematosus: relations with disease activity, antibodies to double stranded DNA, and neutropenia. Ann. Rheum. Dis. 58:309–14.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Baumann I, et al. (2002) Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. Arthritis Rheum. 46:191–201.CrossRefPubMedGoogle Scholar
  7. 7.
    Reefman E, et al. (2006) Is disturbed clearance of apoptotic keratinocytes responsible for UVB-induced inflammatory skin lesions in systemic lupus erythematosus? Arthritis Res. Ther. 8:R156.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Urbonaviciute V, et al. (2008) Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J. Exp. Med. 205:3007–18.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bianchi ME, Agresti A. (2005) HMG proteins: dynamic players in gene regulation and differentiation. Curr. Opin. Genet. Dev. 15:496–506.CrossRefPubMedGoogle Scholar
  10. 10.
    Calogero S, et al. (1999) The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nat. Genet. 22:276–80.CrossRefGoogle Scholar
  11. 11.
    Kazama H, et al. (2008) Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity. 29:21–32.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Scaffidi P, Misteli T, Bianchi ME. (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 418:191–5.CrossRefGoogle Scholar
  13. 13.
    Andersson U, et al. (2000) High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192:565–70.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Youn JH, Oh YJ, Kim ES, Choi JE, Shin J. (2008) High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-α production in human monocytes. 180:5067–74.Google Scholar
  15. 15.
    Wang H, et al. (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science. 285:248–51.Google Scholar
  16. 16.
    Hreggvidsdottir HS, et al. (2009) The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation. J. Leukoc. Biol. 86:655–62.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Schiraldi M, et al. (2012) HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4. J. Exp. Med. 209:551–63.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Straino S, et al. (2008) High-mobility group box 1 protein in human and murine skin: involvement in wound healing. J. Invest. Dermatol. 128:1545–53.CrossRefPubMedGoogle Scholar
  19. 19.
    Mitola S, et al. (2006) Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine. J. Immunol. 176:12–5.CrossRefPubMedGoogle Scholar
  20. 20.
    Van Zoelen MAD, et al. (2009) Role of toll-like receptors 2 and 4, and the receptor for advanced glycation end products in high-mobility group box 1-induced inflammation in vivo. Shock. 31:280–4.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Park JS, et al. (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J. Biol. Chem. 279:7370–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Kokkola R, et al. (2005) RAGE is the major receptor for the proinflammatory activity of HMGB1 in rodent macrophages. Scand. J. Immunol. 61:1–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Palumbo R, et al. (2009) Src family kinases are necessary for cell migration induced by extracellular HMGB1. J. Leukoc. Biol. 86:617–23.CrossRefPubMedGoogle Scholar
  24. 24.
    Palumbo R, et al. (2007) Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-kappaB activation. J. Cell. Biol. 179:33–40.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Venereau E, et al. (2012) Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J. Exp. Med. 209:1519–28.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Yang H, et al. (2010) A critical cysteine is required for HMGB1 binding to toll-like receptor 4 and activation of macrophage cytokine release. Proc. Natl. Acad. Sci. U. S. A. 107:11942–7.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Yang H, et al. (2012) Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). Mol. Med. 18:250–9.CrossRefGoogle Scholar
  28. 28.
    Hreggvidsdottir HS, et al. (2012) High mobility group box protein 1 (HMGB1)-partner molecule complexes enhance cytokine production by signaling through the partner molecule receptor. Mol. Med. 18:224–30.CrossRefPubMedGoogle Scholar
  29. 29.
    Tian J, et al. (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat. Immunol. 8:487–96.CrossRefPubMedGoogle Scholar
  30. 30.
    Urbonaviciute V, et al. (2007) HMGB1-containing nucleosomes released from secondary necrotic cells cause activation and cytokine release from monocytes/macrophages and dendritic cells: implications for the immunopathogenesis of SLE. Ann. Rheum. Dis. 66:A11.Google Scholar
  31. 31.
    Wen Z, et al. (2013) Autoantibody induction by DNA-containing immune complexes requires HMGB1 with the TLR2/microRNA-155 pathway. J. Immunol. 190:5411–22.CrossRefPubMedGoogle Scholar
  32. 32.
    Qing X, et al. (2008) Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: involvement of HMGB1 in anti-DNA antibody-induced renal injury. Immunol. Lett. 121:61–73.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Sun W, et al. (2013) Immune complexes activate human endothelium involving the cell-signaling HMGB1-RAGE axis in the pathogenesis of lupus vasculitis. Lab. Invest. 93:626–38.CrossRefPubMedGoogle Scholar
  34. 34.
    Munoz LE, et al. (2008) Apoptosis in the pathogenesis of systemic lupus erythematosus. Lupus. 17:371–5.CrossRefPubMedGoogle Scholar
  35. 35.
    Bijl M, Reefman E, Horst G, Limburg PC, Kallenberg CG. (2006) Reduced uptake of apoptotic cells by macrophages in systemic lupus erythematosus: correlates with decreased serum levels of complement. Ann. Rheum. Dis. 65:57–63.CrossRefPubMedGoogle Scholar
  36. 36.
    Liu G, et al. (2008) High mobility group protein-1 inhibits phagocytosis of apoptotic neutrophils through binding to phosphatidylserine. J. Immunol. 181:4240–6.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Friggeri A, et al. (2010) HMGB1 inhibits macrophage activity in efferocytosis through binding to the alphavbeta3-integrin. Am. J. Physiol. Cell. Physiol. 299:C1267–76.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Banerjee S, Friggeri A, Liu G, Abraham E. (2010) The C-terminal acidic tail is responsible for the inhibitory effects of HMGB1 on efferocytosis. J. Leukoc. Biol. 88:973–9.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Davis K, et al. (2012) Poly(ADP-ribosyl)ation of high mobility group box 1 (HMGB1) protein enhances inhibition of efferocytosis. Mol. Med. 18:359–69.CrossRefPubMedGoogle Scholar
  40. 40.
    Banerjee S, et al. (2011) Intracellular HMGB1 negatively regulates efferocytosis. J. Immunol. 187:4686–94.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Brinkmann V, et al. (2004) Neutrophil extracellular traps kill bacteria. Science. 303:1532–5.CrossRefGoogle Scholar
  42. 42.
    Brinkmann V, Laube B, Abu Abed U, Goosmann C, Zychlinsky A. (2010) Neutrophil extracellular traps: how to generate and visualize them. J. Vis. Exp. (36):e1724.Google Scholar
  43. 43.
    Kessenbrock K, et al. (2009) Netting neutrophils in autoimmune small-vessel vasculitis. Nat. Med. 15:623–5.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Garcia-Romo GS, et al. (2011) Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3:73ra20.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Lande R, et al. (2011) Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 3:73ra19.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Villanueva E, et al. (2011) Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. Immunol. 187:538–52.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Leffler J, et al. (2013) Degradation of neutrophil extracellular traps co-varies with disease activity in patients with systemic lupus erythematosus. Arthritis Res. Ther. 15:R84.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Carmona-Rivera C, Kaplan MJ. (2013) Low-density granulocytes: a distinct class of neutrophils in systemic autoimmunity. Semin. Immunopathol. 35:455–63.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Tadie JM, et al. (2013) HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4. Am. J. Physiol. Lung Cell. Mol. Physiol. 304:L342–9.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Abdulahad DA, et al. (2011) High mobility group box 1 (HMGB1) and anti-HMGB1 antibodies and their relation to disease characteristics in systemic lupus erythematosus. Arthritis Res. Ther. 13:R71.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Jiang W, Pisetsky DS. (2008) Expression of high mobility group protein 1 in the sera of patients and mice with systemic lupus erythematosus. Ann. Rheum. Dis. 67:727–8.CrossRefPubMedGoogle Scholar
  52. 52.
    Li J, et al. (2010) Expression of high mobility group box chromosomal protein 1 and its modulating effects on downstream cytokines in systemic lupus erythematosus. J. Rheumatol. 37:766–75.CrossRefPubMedGoogle Scholar
  53. 53.
    Ma C, et al. (2012) Elevated plasma level of HMGB1 is associated with disease activity and combined alterations with IFN-alpha and TNF-alpha in systemic lupus erythematosus. Rheumatol. Int. 32:395–402.CrossRefPubMedGoogle Scholar
  54. 54.
    Zickert A, et al. (2012) Renal expression and serum levels of high mobility group box 1 protein in lupus nephritis. Arthritis Res. Ther. 14:R36.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Abdulahad DA, et al. (2012) Urine levels of HMGB1 in systemic lupus erythematosus patients with and without renal manifestations. Arthritis Res. Ther. 14:R184.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Hayashi A, et al. (2009) Lupus antibodies to the HMGB1 chromosomal protein: epitope mapping and association with disease activity. Mod. Rheumatol. 19:283–92.CrossRefPubMedGoogle Scholar
  57. 57.
    de Souza AW, et al. (2013) Is serum HMGB1 a biomarker in ANCA-associated vasculitis? Arthritis Res. Ther. 15:R104.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Urbonaviciute V, et al. (2007) Factors masking HMGB1 in human serum and plasma. J. Leukoc. Biol. 81:67–74.CrossRefPubMedGoogle Scholar
  59. 59.
    Barnay-Verdier S, et al. (2011) Emergence of autoantibodies to HMGB1 is associated with survival in patients with septic shock. Intensive Care Med. 37:957–62.CrossRefPubMedGoogle Scholar
  60. 60.
    Schaper F, Heeringa P, Bijl M, Westra J. (2013) Inhibition of high-mobility group box 1 as therapeutic option in autoimmune disease: lessons from animal models. Curr. Opin. Rheumatol. 25:254–9.CrossRefPubMedGoogle Scholar
  61. 61.
    Dupire G, Nicaise C, Gangji V, Soyfoo MS. (2012) Increased serum levels of high-mobility group box 1 (HMGB1) in primary Sjögren’s syndrome. Scand. J. Rheumatol. 41:120–3.CrossRefPubMedGoogle Scholar
  62. 62.
    Goldstein RS, et al. (2007) Cholinergic anti-inflammatory pathway activity and high mobility group box-1 (HMGB1) serum levels in patients with rheumatoid arthritis. Mol. Med. 13:210–5.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Pullerits R, Urbonaviciute V, Voll RE, Forsblad-D’Elia H, Carlsten H. (2011) Serum levels of HMGB1 in postmenopausal patients with rheumatoid arthritis: associations with proinflammatory cytokines, acute-phase reactants, and clinical disease characteristics. J. Rheumatol. 38:1523–5.CrossRefPubMedGoogle Scholar
  64. 64.
    Schierbeck H, et al. (2013) HMGB1 levels are increased in patients with juvenile idiopathic arthritis, correlate with early onset of disease, and are independent of disease duration. J. Rheumatol. 40:1604–13.CrossRefPubMedGoogle Scholar
  65. 65.
    Taniguchi N, et al. (2003) High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum. 48:971–81.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Wibisono D, et al. (2010) Serum HMGB1 levels are increased in active Wegener’s granulomatosis and differentiate between active forms of ANCA-associated vasculitis. Ann. Rheum. Dis. 69:1888–9.CrossRefPubMedGoogle Scholar
  67. 67.
    Bruchfeld A, et al. (2011) High-mobility group box-1 protein (HMGB1) is increased in antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis with renal manifestations. Mol. Med. 17:29–35.CrossRefPubMedGoogle Scholar
  68. 68.
    Henes FO, et al. (2011) Correlation of serum level of high mobility group box 1 with the burden of granulomatous inflammation in granulomatosis with polyangiitis (Wegener’s). Ann. Rheum. Dis. 70:1926–9.CrossRefPubMedGoogle Scholar
  69. 69.
    Oktayoglu P, et al. (2013) Elevated serum levels of high mobility group box protein 1 (HMGB1) in patients with ankylosing spondylitis and its association with disease activity and quality of life. Rheumatol. Int. 33:1327–31.CrossRefPubMedGoogle Scholar
  70. 70.
    Kanakoudi-Tsakalidou F, et al. (2014) Simultaneous changes in serum HMGB1 and IFN-α levels and in LAIR-1 expression on plasmatoid dendritic cells of patients with juvenile SLE. New therapeutic options? Lupus. 23:305–12.CrossRefPubMedGoogle Scholar
  71. 71.
    Urbonaviciute V, et al. (2009) Oxidation of the alarmin high-mobility group box 1 protein (HMGB1) during apoptosis. Autoimmunity. 42:305–7.CrossRefPubMedGoogle Scholar
  72. 72.
    Kuhn A, Bijl M. (2008) Pathogenesis of cutaneous lupus erythematosus. Lupus. 17:389–93.CrossRefPubMedGoogle Scholar
  73. 73.
    Popovic K, et al. (2005) Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. Arthritis Rheum. 52:3639–45.CrossRefPubMedGoogle Scholar
  74. 74.
    Barkauskaite V, et al. (2007) Translocation of the novel cytokine HMGB1 to the cytoplasm and extracellular space coincides with the peak of clinical activity in experimentally UV-induced lesions of cutaneous lupus erythematosus. Lupus. 16:794–802.CrossRefPubMedGoogle Scholar
  75. 75.
    Abdulahad DA, et al. (2013) High mobility group box 1 (HMGB1) in relation to cutaneous inflammation in systemic lupus erythematosus (SLE). Lupus. 22:597–606.CrossRefPubMedGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

Authors and Affiliations

  1. 1.Department of Rheumatology and Clinical Immunology, AA21, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
  2. 2.Department of Internal Medicine and RheumatologyMartini HospitalGroningenThe Netherlands

Personalised recommendations